The idea that the tumor environment is intrinsically immunogenic and, therefore, contains lymphocytes with the potential to induce tumor regression has led to the use of tumor-infiltrating lymphocytes (TILs) in clinical trials (1-14). In this procedure lymphocytes are grown ex vivo directly from tumors in the presence of the lymphokine interleukin 2 (IL-2); patients are reinfused with their TILs after the latter have been expanded in culture for several weeks. Although 60% of metastatic melanoma patients who had previously received any immunotherapy showed objective responses in the largest clinical TIL trial to date (15), the characteristics of the tumor environment that produces TIL's in vivo remain unclear.
Two classes of stimuli--one derived from cell-cell contact between tumor cells and immunocytes and the other from soluble factors--may influence T-cell homing and proliferation. IL-2 is a potent mitogen for T cells, the cell type of TILs used (Table 1); however, its biosynthesis appears to be confined to immunocytes (16). This facts is consistent with the current belief that immunologically competent cells such as lymphocytes and monocytes represent the major sources of secreted mitogenic stimulation for lymphocytes. In this study the subject of soluble factors secreted by tumor cell lines as sources of stimuli for lymphocyte proliferation was addressed.
As a starting point for this work, the issue of whether a tumor cell line established from a melanoma tumor could stimulate the growth of TILs derived from melanoma masses was examined. After confirming the amplification potential of three melanoma cell lines, a nonmelanoma line was tested for the same bioactivity and found to be at least as potent a mitogenic source; tumor-derived mitogenic activity for TILs could be ascribed to secreted factor(s) as mitogenic activity for TILs was found in its serum-free supernatant. Immunologic and proliferative assays indicate nonidentity of at least one secreted factor with any previously characterized lymphokine.